PANCREATIN MICROCAPSULES

Abstract

The invention relates to a pharmaceutical composition of the cores of microgranules containing pancreatin, cetyl alcohol, poloxamer 407 in predetermined quantities, the production method, as well as the production of the water-based enteric-coated microgranules. Furthermore, the resulting oral dosage form does not contain residual acetone. The technical result is in achieving higher stability of the cores and the enteric-coated microgranules, respectively, while maintaining the good solubility of the enteric-coated microgranules, which allows the application of the claimed pancreatin microgranules for the preparation of safe and non-toxic drugs for the treatment of digestive disorders.

Claims

1. A pharmaceutical composition for the preparation of a drug for the treatment of digestive disorders associated with pancreatic exocrine insufficiency, dyspepsia, pancreatitis, cystic fibrosis, type I diabetes and/or type II diabetes, comprising: Pancreatin in the amount from 95.6 wt % up to 98.0 wt %, Cetyl alcohol in the amount from 1.0 wt % up to 2.3 wt %, Poloxamer 407 in the amount from 1.0 wt % up to 2.1 wt %, in the form of the cores of microgranules with the following sizes: d (core diameter)=1.0-1.2 mm, 1 (core length)=0.8-2.0 mm.

2. A method of production of the pharmaceutical composition according to claim 1, comprising the steps of: a) preparation of a mixture of a binding agent, consisting of three components, which are ethyl alcohol, cetyl alcohol, poloxamer 407 in the following ratios 1:0.11:0.11-1:0.13:0.13, besides, the process is carried out at T=40-45° C. b) mixing pancreatin with ethyl alcohol, followed by the addition of the binding agent obtained in step (a). c) molding and spheronization of the cores of microgranules from the resulting mixture in the presence of ethyl alcohol; d) drying the cores of the microgranules with the possibility of removing ethyl alcohol.

3. The method according to claim 1 where step (d) is carried out at a temperature of not more than 34° C.

4. Pancreatin microgranule containing the pharmaceutical composition according to claim 1 and the enteric coating comprising water, macrogol 4000, talc, an emulsion of simethicone, a suspension of methacrylic acid and ethyl acrylate copolymer in a ratio of 1:1, in a dosage form suitable for oral administration.

5. The application of the cores of pancreatin microgranules according to claim 1 for the preparation of a drug for the treatment of digestive disorders associated with pancreatic exocrine insufficiency, dyspepsia, pancreatitis, cystic fibrosis, type I diabetes and/or type II diabetes.

6. The application of pancreatin microgranules according to claim 4 for the preparation of a drug for the treatment of digestive disorders associated with pancreatic exocrine insufficiency, dyspepsia, pancreatitis, cystic fibrosis, type I diabetes and/or type II diabetes.

Description

THE IMPLEMENTATION OF THE INVENTION

Example 1 (According to the Invention)

[0041] An example illustrates the preparation of a pharmaceutical composition containing pancreatin in the presence of an ethyl alcohol solvent with the possibility of obtaining the cores of microgranules.

[0042] Initially, a solution of the binding agent is prepared.

[0043] According to one implementation of the invention, ethyl alcohol is fed into a manufacturing vessel equipped with a stirrer and a heated jacket at 40-45° C. Then, with stirring, cetyl alcohol (in powder), poloxamer 407 (in powder) are added at a ratio of ethyl alcohol:cetyl alcohol:poloxamer 407-1:0.11:0.11, respectively. Therefore, a ternary mixture of the binding agent is obtained.

[0044] According to one implementation of the invention, ethyl alcohol is fed into a manufacturing vessel equipped with a stirrer and a heated jacket at 40-45° C. Then, with stirring, cetyl alcohol (in powder) and poloxamer 407 (in powder) are added at a ratio of ethyl alcohol:cetyl alcohol:poloxamer 407-1:0.12:0.12, respectively.

[0045] According to another implementation of the invention, ethyl alcohol is fed into a manufacturing vessel equipped with a stirrer and a heated jacket at 40-45° C. Next, with stirring, cetyl alcohol (in powder) and poloxamer 407 (in powder) are added at a ratio of ethyl alcohol:cetyl alcohol:poloxamer 407-1:0.13:0.13, respectively.

[0046] According to one implementation of the invention, pancreatin is loaded into the mixer-granulator, then ethanol is added to improve wetting properties, then the prepared binding agent is loaded into the moistened mixture taking into account the above ratios at ambient temperature. After each supply of one of the components, the mixture is thoroughly stirred. The defined consistent supply of ingredients, in particular, pre-mixing pancreatin with ethyl alcohol, ensures uniform dissolution of the components and more efficient interaction of the components in the cores of microgranules.

[0047] The resulting mixture was loaded for extrusion using dies with a hole size of 1.0 mm and with a controlled temperature of granules at 30° C. The resulting cores with a diameter from 1.0 to 1.2 mm and length from 0.8 to 2.0 mm are fed to the spheronization step, which is carried out in the presence of an ethyl alcohol solvent with a concentration of 55-96 wt %, with a ratio of pancreatin to ethyl alcohol of 1:0.38.

[0048] During the method implementation, the cores of microgranules are obtained, the composition of which is given in the Table.

TABLE-US-00001 TABLE 1 The composition of the cores of microgranules, in wt % 1 Pancreatin 95.6 96.00 96.55 96.85 97.50 98.00 2 Cetyl alcohol 2.30 2.00 1.50 1.57 1.25 1.00 3 Poloxamer 407 2.10 2.00 1.95 1.57 1.25 1.00 Core Diameter (Ø) of the cores of 1.00 1.00 1.20 1.10 1.15 1.10 sizes microgranules, mm The length (l) of the cores of 0.80 1.00 1.30 1.15 1.20 2.00 microgranules, mm

[0049] After spheronization, the obtained cores of microgranules are subjected to drying, which is carried out at a temperature of 34° C., humidity 2-5 wt %. The dried cores are fed for the next applying of the enteric coating solution.

[0050] The enteric coating solution is prepared by mixing of the ingredients:water, macrogol 4000, talc, a 30% emulsion of simethicone, a suspension of methacrylic acid and ethyl acrylate copolymer (1:1) (dispersion 30%) at a ratio of 1:0.03:0.14:0.004:1.04. Application of the prepared solution on the cores of microgranules is carried out by spraying on granules preheated to 35° C. with a ratio of microgranules to the resulting solution of 1:1.57. At the end of the step of applying the enteric coating solution, the obtained microgranules are dried while maintaining the temperature in the range from 35° C. to 50° C.

Example 2 (Comparative by the Method of Producing the Cores of Microgranules)

[0051] The method for producing the cores of pancreatin microgranules, as in Example 1, with the difference that, first of all, ethyl alcohol is loaded into the mixer-granulator, and pancreatin is added in portions, then the binding agent is added in the ratios indicated in Example 1. After each supply of one of the components, the mixture is thoroughly mixed for 15 minutes.

Example 3 (Comparative by the Method of Producing the Cores of Microgranules)

[0052] The method for producing the cores of pancreatin microgranules, as in Example 1, with the difference that the prepared mixture of pancreatin with the binding agent is loaded into the hopper of a molding machine. The suspension is granulated using dies with hole sizes of 1.0 mm with a controlled drying temperature of the cores at 28° C.

Example 4 (Comparative by the Method of Producing the Cores of Microgranules)

[0053] The method for producing the cores of pancreatin microgranules, as in Example 1, with the difference that the prepared mixture of pancreatin with the binding agent is loaded into the hopper of a molding machine. The suspension is granulated using dies with a hole size of 1.0 mm with a controlled drying temperature of the cores at 41° C.

Example 5 (Comparative by the Method of Producing the Cores of Microgranules)

[0054] The method for producing the cores of pancreatin microgranules, as in Example 1, with the difference that the prepared mixture of pancreatin with the binding agent is loaded into the hopper of a molding machine. The suspension is granulated using dies with a hole size of 1.0 mm with a controlled drying temperature of the cores at 38° C.

Example 6 (According to the Invention)

[0055] The method of producing pancreatin microgranules according to Example 1 with the difference that the ratio of the ingredients in the solution of the enteric coating—water, macrogol 4000, talc, a 30% emulsion of simethicone, a suspension of methacrylic acid and ethyl acrylate copolymer (1:1) (dispersion 30%)— is in a ratio of 1:0.03:0.16:0.004:1.03. The resulting solution was stirred for 15 minutes.

Example 7 (Comparative with the Prototype)

[0056] The method of producing micropellets according to the prototype where acetone was used as a solvent in the preparation of the enteric coating.

[0057] 1. Preparation of Pancreatin Micropellets:

[0058] 1.59 kg of pancreatin was mixed with 0.25 kg of polyethylene glycol 4000 in a mixer, thoroughly moistened with 0.25 kg of 2-propanol. The resulting mixture was molded with an inner diameter of 1.0 mm. During pressing, the temperature was below 50° C. The resulting 1.46 kg of pancreatin after molding, in equal portions, were sent to the spheronization step for obtaining the cores of micropellets. During spheronization, about 13.5 g of 2-propanol was added. After drying at a temperature in the range from 35 to 50° C. for 12 h, pancreatin microgranules were sorted by sieving on sieves.

[0059] 2. Applying of the Enteric Coating:

[0060] The coating solution was prepared by adding with stirring 231.4 g of hydroxypropyl methylcellulose phthalate, 12.85 g of triethyl citrate, 4.89 g of cetyl alcohol, and 5.55 g of dimethicone 1000 to 2000 g of acetone at room temperature. The coating was applied until film formation by spraying the resulting solution on pancreatin micropellets. The temperature of the cores of micropellets during coating was maintained in the range from 37 to 43° C. Then the obtained micropellets were dried at a temperature in the range from 35 to 50° C. for 12 hours.

[0061] Stability Test of Pancreatin Microgranules Obtained According to the Present Invention

[0062] For the cores of pancreatin microgranules, obtained by the methods that are described in Examples 1-7, the stability tests were carried out under conditions simulating the environment of the stomach at pH=1.0 and the environment of the upper intestine at pH=6.0. The determination of the amount of active substance, which for a certain period of time must be released into the dissolution medium from a solid dosage form, was carried out by the biochemical method, in accordance with the SP XIII GPM 1.4.2.0014.15 “Dissolution for solid pharmaceutical dose forms” at pH=1.0 and pH=6.0.

[0063] The Dissolution test is carried out in two steps.

[0064] Step 1 (acidic, i.e. pH=1.0) using an impeller mixer.

[0065] 4M sodium hydroxide solution. 16.0 g of sodium hydroxide is placed in a 100 ml volumetric flask, dissolved in 80 ml of water, the temperature in the range of 37±0.5° C. After cooling the solution to room temperature, the solution is diluted to the necessary volume and mixed. The test time is 120 minutes.

[0066] Step 2 (alkaline, i.e. pH=6.0) using an impeller mixer.

[0067] A phosphate buffer solution at pH=6.0, in which 2.0 g of sodium chloride and 9.2 g of monosubstituted potassium phosphate are placed in a 1000 ml volumetric flask and dissolved in approximately 950 ml of water. The pH of the solution is adjusted potentiometrically to 6.0 using a 4M sodium hydroxide solution, the solution is diluted to the necessary volume, temperature 37±0.5° C. The dissolution process lasts for 30 minutes.

[0068] The average values obtained during the testing of samples at pH=1.0 for 120 minutes and at pH=6.0 for 30 minutes are shown in Tables 2-4.

[0069] The dissolution stability characteristics under conditions simulating the gastric environment of the prepared samples are given as the percentage of residual lipolytic activity after incubation in terms of the actual lipolytic activity of the samples tested before incubation.

[0070] According to the above GPM “Dissolution for solid pharmaceutical dose forms”, the amount of active substance released into the dissolution medium when released in the stomach should not exceed 10% of the claimed content of pancreatin; in the environment of the upper intestine should be at least 75% of the claimed content of pancreatin.

[0071] Lipolytic activity was determined by the biochemical method, in comparison with the specific activity of pancreatin enzymes of a standard sample. Lipolytic activity is determined by comparing the rate at which a suspension of pancreatin microgranules hydrolyzes an olive oil emulsion substrate with the rate at which a suspension of a standard pancreatin (lipase) sample hydrolyzes the same substrate under the same conditions.

[0072] Comparison of the dissolution stability indicators of pancreatin microgranules under conditions simulating the environment of the stomach and the environment of the upper intestine according to Examples 1 and 2.

TABLE-US-00002 TABLE 2 The dissolution stability of pancreatin microgranules under conditions simulating the environment of the stomach (at pH = 1.0) and upper intestine (at pH = 6.0) Samples of microgranules prepared according to Stability of samples examples of the invention at pH = 1.0, % At pH = 6.0, % The core of microgranules 4.6 93.7 according to Example 1 The core of microgranules 6.8 83.8 according to Example 2

[0073] The results of the Dissolution test indicates that the gastric acid resistance of the composition according to Example 1 at pH=1.0 and pH=6.0 exceeds the stability indices of the composition obtained in Example 2. The stability of the samples at pH=1 should be no more than 10%, which is a control option.

[0074] In accordance with the general article of pharmacopoeia of the State Pharmacopoeia XIII, OFS, 1.4.2.0014.15 “Dissolution for solid dosage forms”, the amount of active substance released into the dissolution medium when released in the stomach should be no more than 10% of the claimed content of the pancreatin; in the environment of the upper intestine must be at least 75% of the claimed content of pancreatin.

[0075] Comparison of the dissolution stability indicators of pancreatin microgranules under conditions simulating the environment of the stomach and the environment of the upper intestine according to Examples 3, 4, and 5.

TABLE-US-00003 TABLE 3 Dissolution stability of pancreatin microgranules under conditions simulating the environment of the stomach (pH = 1.0) and the environment of the upper intestine (pH = 6.0) Sample pH 1.0% pH 6.0, % The core of microgranules 6.1 87.3 according to Example 3 The core of microgranules 7.0 84.6 according to Example 4 The core of microgranules 6.4 89.5 according to Example 5

[0076] The obtained results of comparison of the dissolution stability indicators of pancreatin microgranules under conditions simulating the stomach and upper intestine environment, for compositions prepared according to Examples 3, 4 and 5, when comparing different temperatures of drying, clearly show the advantage of the selected temperature at 34° C. for drying the cores of microgranules after spheronization.

[0077] Comparison of the results of gastric acid resistance tests at pH=1.0 and pH=6.0 of the composition prepared according to Examples 1 and 2 and the prototype.

TABLE-US-00004 TABLE 4 Dissolution stability of pancreatin microgranules under conditions simulating the environment of the stomach (pH = 1.0) and the environment of the upper intestine (pH = 6.0) Sample pH 1.0, % pH 6.0, % The core of microgranules 4.6 93.7 according to Example 1 The core of microgranules 6.8 83.8 according to Example 2 The core of microgranules 5.9 86.8 according to the prototype

[0078] The results of comparing the stability indicators of pancreatin microgranules when dissolved under conditions simulating the environment of the stomach and the environment of the upper intestine, the compositions made according to Examples 1 and 2 show the advantages of the proposed method for producing the pharmaceutical composition of the cores of microgranules compared to the prototype composition.

[0079] Therefore, it was found that the tested samples of pancreatin microgranules are resistant to gastric acid at pH=1.0, and their activity is not less than:

[0080] 4.6% (even more preferred value) for the sample prepared according to Example 1;

[0081] 7.0% (preferred value) for the sample prepared according to Example 4;

[0082] 6.8% (preferred value) for the sample prepared according to Example 2;

[0083] 6.4% (more preferred value) for the sample prepared according to Example 5;

[0084] 6.1% (more preferred value) for the sample prepared according to Example 3;

[0085] from a predetermined lipolytic activity of the pancreatin standard.

[0086] The pancreatin microgranules in the present invention are stable when released in the upper intestine at pH=6.0, and the yield is not less than:

[0087] 93.7% (even more preferred value) for the sample prepared according to Example 1;

[0088] 89.5% (more preferred value) for the sample prepared according to Example 5;

[0089] 87.3% (more preferred value) for the sample prepared according to Example 3;

[0090] 84.6% (preferred value) for the sample prepared according to Example 4;

[0091] 83.8% (preferred value) for the sample prepared according to Example 2;

[0092] from a predetermined lipolytic activity of the pancreatin standard.

[0093] The storage stability of the cores of pancreatin microgranules shows good results.

[0094] Unexpectedly, it was found that the enteric water-based coating is not inferior in its properties to an acetone-based coating. Subsequently, applying the enteric coating on pancreatin microgranules in the presence of an aqueous solvent positively affects the storage stability of the pharmaceutical composition at control points.

TABLE-US-00005 TABLE 5 The storage stability of the cores of pancreatin microgranules within 90 and 180 days Stability Stability Stability Stability at pH = at pH = at pH = at pH = 1.0, %, 6.0, %, 1.0, %, 6.0, %, Sample 90 days 90 days 180 days 180 days The core of microgranules 4.1 89.3 4.9 90.5 according to Example 1 The core of microgranules 6.8 80.7 6.5 81.8 according to Example 2 The core of microgranules 5.2 84.7 5.1 83.4 according to Example 3 The core of microgranules 6.3 82.2 6.0 80.9 according to Example 4 The core of microgranules 5.6 85.7 5.3 87.0 according to Example 5 The core of microgranules 5.4 82.1 5.9 89.6 according to Example 6 The core of microgranules 5.9 88.4 6.2 87.1 according to the prototype